HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 291/4/R970    most recent 00793.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Levy, R. M. Articles by Billiar, T. R. Search for Related Content PubMed PubMed Citation Articles by Levy, R. M. Articles by Billiar, T. R.

INFLAMMATION AND CYTOKINES

Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4

¹Department of Surgery and ²Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 10 November 2005 ; accepted in final form 26 April 2006

Extensive soft tissue injury and bone fracture are significant contributors to the initial systemic inflammatory response in multiply injured patients. Systemic inflammation can lead to organ dysfunction remote from the site of traumatic injury. The mechanisms underlying the recognition of peripheral injury and the subsequent activation of the immune response are unknown. Toll-like receptors (TLRs) recognize microbial products but also may recognize danger signals released from damaged tissues. Here we report that peripheral tissue trauma initiates systemic inflammation and remote organ dysfunction. Moreover, this systemic response to a sterile local injury requires toll-like receptor 4 (TLR4). Compared with wild-type (C3H/HeOuJ) mice, TLR4 mutant (C3H/HeJ) mice demonstrated reduced systemic and hepatic inflammatory responses to bilateral femur fracture. Trauma-induced nuclear factor (NF)-B activation in the liver required functional TLR4 signaling. CD14^–/– mice failed to demonstrate protection from fracture-induced systemic inflammation and hepatocellular injury. Therefore, our results also argue against a contribution of intestine-derived LPS to this process. These findings identify a critical role for TLR4 in the rapid recognition and response pathway to severe traumatic injury. Application of these findings in an evolutionary context suggests that multicellular organisms have evolved to use the same pattern recognition receptor for surviving traumatic and infectious challenges.

trauma; innate immunity; liver injury; CD14

This article has been cited by other articles:

				D. J. Kaczorowski, K. P. Mollen, R. Edmonds, and T. R. Billiar Early events in the recognition of danger signals after tissue injury J. Leukoc. Biol., March 1, 2008; 83(3): 546 - 552. [Abstract] [Full Text] [PDF]

				B. Salvesen, M. Fung, O. D. Saugstad, and T. E. Mollnes Role of Complement and CD14 in Meconium-Induced Cytokine Formation Pediatrics, March 1, 2008; 121(3): e496 - e505. [Abstract] [Full Text] [PDF]

				K. P. Mollen, R. M. Levy, J. M. Prince, R. A. Hoffman, M. J. Scott, D. J. Kaczorowski, R. Vallabhaneni, Y. Vodovotz, and T. R. Billiar Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells J. Leukoc. Biol., January 1, 2008; 83(1): 80 - 88. [Abstract] [Full Text] [PDF]

				R. M. Levy, K. P. Mollen, J. M. Prince, D. J. Kaczorowski, R. Vallabhaneni, S. Liu, K. J. Tracey, M. T. Lotze, D. J. Hackam, M. P. Fink, et al. Systemic inflammation and remote organ injury following trauma require HMGB1 Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1538 - R1544. [Abstract] [Full Text] [PDF]